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Tuesday, February 26, 2013

Functional Cure of Chronic Hepatitis B: RNAi Therapeutics May Be the Only Game in Town (Part I)

Today, I wanted to post the first of a two-part series on the hepatitis B virus (HBV) candidate by Arrowhead Research which is set to enter clinical development in the first half of this year. But as if on cue, the company just announced the publication of extremely potent ('multi-log') reductions in gene expression with their systemic DPC delivery technology. This thus bodes very well for what is shaping up to be an RNAi Therapeutics pipeline highlight: ARC520 for the treatment of chronic hepatitis B viral (HBV) infection.

Are you wondering what could be the next HCV-type or maybe even larger drug development
opportunity? HBV may well be the new
HCV. With HCV increasingly curable, the pharmaceutical industry has increased appetite for finally also developing a cure for chronic HBV. Based on the potent
preclinical data with DPC delivery technology and the view of thought
leaders in the field that the specific suppression of HBV proteins may be the single most promising mechanism by which this can be
achieved, I am more and more thrilled by
the prospect that ARC520 could
become a poster child for an RNAi Therapeutics that addresses a major public
health burden.

In anticipation of the March webinar by Arrowhead where the
company wants to talk more about the concept behind ARC520 and their most
recent data on the drug candidate, two blog entries over the coming week will
first explain the rationale for why HBV is such an attractive RNAi Therapeutics
opportunity and then discuss the features that make ARC520 a particularly promising (including in a commercial sense) RNAi Therapeutics
candidate.

Only RNAi Can
Suppress HBV Proteins in a Specific, Potent, and Rapid Manner

About 2 billion worldwide are infected with hepatitis B
virus (HBV). 300-400 million of these have subsequently developed chronic HBV, meaning that they are at
increased risk of prematurely dying from liver-related complications such as
cirrhosis and liver cancer. Every year, more than one million chronic HBV
patients die of such complications. In
East Asia and developing countries where mother-to-child transmission is the
predominant (and highly effective from a viral point of view) mode of
infection, HBV is responsible for more than half of primary liver cancers; in
Western countries where transmission largely occurs via body fluids,
esp. blood, it still accounts for about one quarter of cases.

This means that the public health burden of chronic HBV
infection already surpasses that of HCV and is extending its lead as the new direct antiviral agents against HCV prove quite effective at eliminating HCV. An
important difference between HBV and HCV is that HBV is a DNA virus that will
persist for life in hepatocytes. This explains we can only dream of a ‘functional’
cure, not a cure full-stop. HCV, by contrast, is an RNA virus which, in the absence of replication, will
disappear due to the relative instability of RNA.

Vaccination works almost 100% well to protect us from HBV infection. but its therapeutic application so far has failed and it also does not address mother-to-child transmission. Interferon and viral polymerase inhibitors (nucs) are currently only recommended
for those with active chronic HBV as determined by increased liver enzyme
levels in the presence of HBV. These drugs, however, only work
to convert 10-30% of those treated into the inactive carrier state with normalized liver enzymes and very little HBV DNA in the blood. Nucs have the
added benefit of very effectively inhibiting active viral replication, meaning
that it does a good job at minimizing the ongoing inflammation in the liver. Unfortunately, only very few of these
patients can be considered to be cured and they are thus still at risk for viral
re-emergence.

It is widely accepted that a functional cure for chronic
HBV, meaning viral suppression in the absence of drug treatment, can only be
achieved by harnessing adaptive immunity. Here, the
name of the game is achieving hepatitis B surface antigen (HBsAg) seroconversion, meaning the development of
antibodies to HBsAg. People who stably carry such antibodies can be considered cured. Although the exact
mechanism by which this is supposed to occur is being debated, it is widely
accepted that immune exhaustion due
to the presence of abundant HBsAg in the serum in the
form of subviral particles and in the liver is the cause of why our immune system tolerates HBV,
instead of eradicating it.

While nucs, which inhibit viral polymerase, not mRNA transcription of viral mRNA which is performed by our own
RNA polymerase II off the viral cccDNA, and interferon can have some suppressive effect on HBsAg levels
(on the order of ½ log), it seems that RNAi Therapeutics is the only means to achieve the specific, potent, and rapid inhibition of HBsAg that is considered to be necessary for a
successful relief from immune exhaustion. In
doing so, an RNAi Therapeutics can do everything that a nuc can do and
more. This means that such an RNAi
Therapeutic may also significantly expand the pool of chronic HBV patients on
therapy and should become a core component in any combination therapy such as
with an interferon.

Look out for the next post on why I think ARC520 is an excellent RNAi Therapeutics candidate to achieve the stated objective.

6 comments:

Anonymous
said...

Dirk,

After reading an article in Molecular Therapy, I am not impressed with DPC at all.

First, it seems DPC is an IV and not a SubQ.

Second, it is not as potent as it has been hyped. DPC has two components - NAG-MLP & chol-siRNA. It requires 2 mg/kg of chol-siF7 & 8 mg/kg of NAG-MLP to achieve 99% of knockdown for F7. That is a very high dose. LNP or GalNAc would be better than DPC.

Thanks for the comment. I am planning to read that paper asap. However, keep in mind that there are now subQ versions of DPCs that have been validated in monkeys (OTS 2012), meaning that the transition of ARC520 from i.v. to subQ is an obvious life-cycle, market-expanding opportunity(incl. extended patent life).

i jst read your article and am impressed,but i want to ask you a question. I got to know that i'm HBVpositive last weej. Since then i hv gone for several test which confirmed that my liver is stil in order. I want to know,does it mean that it's at acute stage? I also read that the virus is self limited. Pls advice me asap.

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